Abstract
Thioredoxin-interacting protein (TXNIP) is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (TXN). Shiga-Y5 (SY5), a fluorine-19 magnetic resonance probe for detecting amyloid-β deposition in the brain, previously showed therapeutic effects in a mouse model of Alzheimer’s disease; however, the mechanism of action of SY5 remains unclear. SY5 passes the blood–brain barrier and then undergoes hydrolysis to produce a derivative, Shiga-Y6 (SY6), which is a TXNIP-negative regulator. Therefore, this study investigates the therapeutic role of SY5 as the prodrug of SY6 in the thioredoxin system in the brain of a mouse model of Alzheimer’s disease. The intraperitoneal injection of SY5 significantly inhibited TXNIP mRNA (p = 0.0072) and protein expression (p = 0.0143) induced in the brain of APP/PS1 mice. In contrast, the levels of TXN mRNA (p = 0.0285) and protein (p = 0.0039) in the brain of APP/PS1 mice were increased after the injection of SY5. The ratio of TXN to TXNIP, which was decreased (p = 0.0131) in the brain of APP/PS1 mice, was significantly increased (p = 0.0072) after the injection of SY5. These results suggest that SY5 acts as a prodrug of SY6 in targeting the thioredoxin system and could be a potential therapeutic compound in oxidative stress-related diseases in the brain.
Highlights
Thioredoxin-interacting protein (TXNIP) plays an important role in the redox system, but it is implicated differently in many diseases, including cancers, diabetes, and neurodegenerative disorders [1]
TXNIP expression is highly triggered by glucose and is increased in the beta-cells (β-cells) of patients with diabetes [3], inhibiting TXN function and inducing increased levels of freely diffusible molecular hydrogen peroxide; it contributes to oxidative stress and eventually β-cell death [4]
Studies showed that TXNIP inhibition prevented β-cell apoptosis and protected against diabetes [5,6]
Summary
Thioredoxin-interacting protein (TXNIP) plays an important role in the redox system, but it is implicated differently in many diseases, including cancers, diabetes, and neurodegenerative disorders [1]. TXNIP expression is highly triggered by glucose and is increased in the beta-cells (β-cells) of patients with diabetes [3], inhibiting TXN function and inducing increased levels of freely diffusible molecular hydrogen peroxide; it contributes to oxidative stress and eventually β-cell death [4]. Studies showed that TXNIP inhibition prevented β-cell apoptosis and protected against diabetes [5,6]. Recent studies have demonstrated that TXNIP protein presenilin 1 (APP/PS1) transgenic mice and primary cultured mouse cerebral cortex neurons HT22 mouse hippocampal cells treated with Aβ peptide [16]. 2. ReSsuevltesral studies have demonstrated the therapeutic effect of curcumin, as seen by the 2in.1c.reGaesneedETxXprNespsiroonteoifnTeXxpNreasnsdioTnX[2N6I]Pand decreased TXNIP protein expression [27] in cells cdmwsSesuuautxhonnueinpbiscdcrdgeejoelceeaeyOrsocrw-iaoegsYtsfurdesoheo.S6rsdlroeYtTap(etoswtSth5hroeYsheehied(asov6i2dyBcg)xi0afidrBohti(0innhdruFfBdogimdaiascglalttieysucguinfSdtvutsc/rugeYi,keotesrdg5tssis1hiyneui)tncpnergw)uatheargnsbtsssaaahhisedsrlsvn.foeaseegaetisAwfsnnbdnoSteorrtdhmcYwdahuueot5iiahsarnnpnbtciseeilinlunaastgoqgdotmscjaoeeuemittdccrpiniiinnetacvi–reicdktgooebdealrndrrbdyaeenaeuysritditgrniicnhvaceiuenpauAmablpttartlSaPruioorttYvarihoPtvmorpee6de/ieniePe;wrdndsrruoSth,ioir1ne(tgtoaseoBhxmewTnsnoBpstdXoefBierhcifaeNvSn)eetl2s,YhedIsc0ia[rPen6i2ua0,noj3recceidtnmb]sexhec.orptrtaegaIhiennnr[/ob2eempkiancts8rgolmhsae]ya(si.iwclicsoess.hOpiicitnassdbhao)ust.i.lnyurgneIrtAtilndorespcmoelfxymutertsuh,eeerltapttreaeclrhnuirhtem2nbeedramgedarhisnranlmc,aaoiaiieavtmsinunehnlrmel’ddpyeesssr coefraecbtriaolncoofrtSeYx5, tthoeinThXibNitmTXRNNIAP,lelevaedl iwngastoutnhcehtahnegreadpeiuntAicPePff/ePcSt1inmthiceeAcoDmmpoadreedl mwiicteh. We investigated the role of SY5 as the prodrug of SY6 in the thioredoxin system, which might be a possible target for intervention in AD
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